Copper-Catalyzed Dehydrogenative Formal [4 + 2] and [3 + 2] Cycloadditions of Methylnaphthalenes and Electron-Deficient Alkenes

Article abstract of DOI:10.1021/acs.orglett.7b03194

Higher π-extended naphthalene, contained in methylnaphthalenes, which could capture alkyl radicals via SOMO-LUMO interactions, enabled the development of Cu-catalyzed formal [4 + 2] and [3 + 2] cycloadditions between methylnaphthalenes and electron-deficient alkenes. Under copper catalysis, a series of electron-deficient alkenes and methylnaphthalenes with different substituents were successfully incorporated with di-tert-butyl peroxide (TBP) as an oxidant and radical initiator, providing a wide range of cycloadducts.

Full text of DOI:10.1021/acs.orglett.7b03194

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Copper-Catalyzed Dehydrogenative Formal [4 + 2] and [3 + 2]
Cycloadditions of Methylnaphthalenes and Electron-Deficient
Alkenes
Guiping Qin,†,§ Yong Wang,† and Hanmin Huang*,†,‡
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
‡Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China
§University of Chinese Academy of Sciences, Beijing 100049, P. R. China
S
* Supporting Information
ABSTRACT: Higher π-extended naphthalene, contained in
methylnaphthalenes, which could capture alkyl radicals via
SOMO−LUMO interactions, enabled the development of Cu-
catalyzed formal [4 + 2] and [3 + 2] cycloadditions between
methylnaphthalenes and electron-deficient alkenes. Under
copper catalysis, a series of electron-deficient alkenes and
methylnaphthalenes with different substituents were success-
fully incorporated with di-tert-butyl peroxide (TBP) as an oxidant and radical initiator, providing a wide range of cycloadducts.
the synthesis of complex targets. With new concepts continually
emerging for radical-involved transformations,5 an intriguing
alternative approach to carbocycles could involve considering
the possibility of radical-triggered cycloaddition reactions with
simple and easily obtained hydrocarbons as starting materials.
In this context, we reasoned that the radical addition/trapping/
oxidative termination sequence would be a promising strategy
for cycloaddition (Scheme 1b).
arbocycles are ubiquitous structural motifs found in many
Cnatural products and synthetic pharmaceutical agents. In
light of their wide existence, carbocycle construction is one of
the enduring and crucial goals of organic synthesis.1 The classic
Diels−Alder reaction and dipolar cycloaddition have been
extensively utilized as powerful cyclization approaches to six-
and five-membered carbocycles (Scheme 1a).2,3 However, since
these reactions are enslaved by the HOMO−LUMO gap
between the coupling partners,4 active dienes and special active
1,3-dipoles are generally required, limiting their broader use in
Benzyl-type radicals are versatile reactive species that can be
generated from simple toluene and its analogues. The electron-
rich property enables benzylic radicals to be excellent electron
donors and moderate acceptors, rendering them ready to be
added to electron-deficient alkenes to give rise to new alkyl
radical species for establishing a series of radical-oxidative relay
transformations.6,7 As shown in Scheme 1c, a newly formed
alkyl radical such as II could be oxidized by an appropriate
oxidant to furnish an oxidative coupling reaction between two
C−H bonds.7c Building upon these findings, we reasoned that
the appropriate aromatics inherent in the benzyl-type radicals
could act as electron acceptors to capture the newly formed
alkyl radical II to furnish an intermolecular cycloaddition
reaction between alkenes and simple hydrocarbons. On the
basis of the resulting mechanistic insight, the key point to
realize the above-mentioned idea is the identification of an
appropriate hydrocarbon that not only can produce benzyl-type
radicals but also contains an arene possessing lower-energy
antibonding π orbitals to facilitate single-electron transfer via
the SOMO−LUMO interaction.8 In this context, we surmised
that methylnaphthalenes containing a higher π-extended
Scheme 1. New Strategy for Constructing Carbocycles via
Radical-Redox Relay
Received: October 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03194
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
naphthalene would be suitable substrates to fulfill such requests,
since their relatively lower-energy antibonding π orbitals could
capture II quickly to suppress the oxidative coupling.9 Herein
we disclose novel Cu-catalyzed formal radical [4 + 2] and [3 +
2] cycloadditions of simple methylnaphthalenes and electron-
deficient alkenes that lead to functionalized polycyclic
compounds, structural motifs common in natural products
and synthetic compounds (Scheme 1d).10
the absence of either copper catalyst or 2-acetoxybenzoic acid
(entries 16−18), indicating the importance of the copper
catalyst and acid additive to promote the reaction.
With the practical catalyst system identified, we examined the
alkene scope of this cycloaddition with 2a as the standard
methylnaphthalene (Scheme 2). α,β-Unsaturated Weinreb
a
Scheme 2. Substrate Scope for the Cycloaddition
Our studies began with the formal [4 + 2] cycloaddition for
the formation of 3aa using (E)-N-methoxy-N-methylcinnama-
mide (1a) and 1-methylnaphthalene (2a) as model substrates.
In the presence of 10 mol % Cu(i-PrCO2)2, 20 mol % HOAc,
and 3.0 equiv of TBP at 120 °C, the desired cycloaddition
adducts 3aa and 4aa were isolated in 70% yield as a mixture
with 90/10 regioselectivity. The structure of the major product
3aa was directly corroborated by single-crystal X-ray diffraction
analysis.11 Moreover, the structure of the minor adduct 4aa was
also confirmed by X-ray diffraction analysis of the correspond-
ing aldehyde obtained through simple functional group
transformation (see the Supporting Information (SI)). The
reaction proceeded in a highly diastereoselective way with
complete trans diastereoselectivity. Carboxylic acids were found
to be effective in promoting the desired transformation, with 2-
acetoxybenzoic acid (A1) serving as the most effective additive
at 120 °C (Table 1, entries 1−5). 2-Acetoxybenzoic acid may
facilitate the genernation of tert-butoxyl radical by accelerating
the decomposition of TBP. Upon examination of different
copper salts (entries 5−15), Cu(OAc)2/2-acetoxybenzoic acid
was found to be the most general and efficient catalytic system
and was chosen as the standard conditions (entry 15). Only
lower yields were obtained when the reaction was conducted in
a
Table 1. Optimization of the Reaction Conditions
b
c
d
entry
[Cu]
acid
yield (%)
3aa/4aa
1
2
Cu(i-PrCO2)2
Cu(i-PrCO2)2
Cu(i-PrCO2)2
Cu(i-PrCO2)2
Cu(i-PrCO2)2
CuCl
CH3CO2H
70
43
28
71
74
62
54
27
66
75
71
66
67
43
76
63
25
17
90/10
88/12
89/11
91/9
Cl3CCO2H
3
(CH2CO2H)2
4
PhCO2H
A1
5
91/9
6
A1
88/12
88/12
88/12
87/13
89/11
88/12
88/12
89/11
87/13
92/8
7
CuF2
A1
8
CuCl2
A1
9
Cu(TFA)2
Cu(OAc)2
Cu(HCO2)2
Cu(acac)2
Cu(tfacac)2
Cu(hfacac)2
Cu(OAc)2
Cu(OAc)2
−
A1
10
11
12
13
14
A1
a
Reaction conditions: 1 (0.4 mmol), 2 (4.0 mmol), TBP (3.0 equiv),
A1
Cu(OAc)2 (10 mol %), and 2-acetoxybenzoic acid (10 mol %) at 120
°C under N2 for 24 h. Isolated yields for 3 and 4 are shown; the data in
parentheses are 3/4 ratios, which were determined by GC−MS or 1H
A1
A1
A1
b
NMR analysis. Isolated yield of 3.
e
15
A1
16
17
−
A1
91/9
amides, such as 1a−n, all underwent formal [4 + 2]
cycloaddition and readily afforded the desired cycloadducts
(3aa−na) in 35−78% yield with good to excellent selectivities.
The efficient formation of the desired adducts illustrated that
either electron-rich or electron-deficient substituents were
tolerated on the aryl ring. In general, alkenes bearing
electron-withdrawing groups provided higher yields than
those containing electron-donating substituents. For example,
87/13
89/11
e
18
−
−
a
Reaction conditions: 1a (0.4 mmol), TBP (3.0 equiv), [Cu] (10 mol
%), additive (20 mol %), and 2a (4.0 mmol) at 120 °C under N2 for
24 h. A1 = (2-CH3CO2)PhCO2H. Isolated yields. Determined by
GC and GC−MS analysis. 2-Acetoxybenzoic acid (10 mol %) was
used.
b
c
d
e
B
DOI: 10.1021/acs.orglett.7b03194
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the reactions of substrates with electron-withdrawing sub-
stituents such as −CF3 and −NO2 at the 4-position of the
benzene ring proceeded smoothly to provide the cycloadducts
in >70% yield (3ka and 3la). Typical functional groups such as
alkyl (1b−d), alkoxy (1e), fluoro (1f), chloro (1g−i), bromo
(1j), trifluoromethyl (1k), and nitro (1l) were well-tolerated
under the optimized reaction conditions. In addition to phenyl-
substituted alkenes, a naphthyl-substituted α,β-unsaturated
Weinreb amide (1m) and a pyridine-substituted α,β-unsatu-
rated Weinreb amide (1n) were also compatible with this new
reaction, generating the corresponding carbocycles (3ma and
3na) in moderate to good yields with good regioselectivities.
The cycloaddition reaction is not limited to α,β-unsaturated
Weinreb amides, as cinnamates (1o and 1p), cinnamamide
(1q), and enones (1r−w) could also be used as coupling
partners in these reactions, giving the corresponding cyclo-
addition products (3oa−wa) in 45−57% yield. Notably, the
two regioisomers produced from the reactions of 1o−w can be
easily separated to provide the pure cycloadducts for further
elaboration.11 We next examined the scope of methylnaph-
thalenes in the Cu-catalyzed cycloaddition reactions (Scheme
2). Various types of 1-methylnaphthalenes 2 were readily
employed and afforded the desired cycloadducts in moderate to
good yields (48−70%) with good regioselectivities (>95/5).
Interestingly, a second methyl group at the 2-, 4-, or 5-position
of the naphthalene ring could be tolerated. Moreover, a labile
substituent such as a bromo group (3le) was tolerated under
the present reaction conditions, thus offering an additional
opportunity for further manipulation of the products obtained.
Meanwhile, we were pleased to observe that 2-methylnaph-
thalene could also be used as a coupling partner to react with
enones and cinnamates to establish a formal [3 + 2]
cycloaddition reaction. However, compared with the formal
[4 + 2] cycloaddition reaction, the formal [3 + 2] cycloaddition
reaction afforded the corresponding products with relatively
lower yields (7uf, 22%; 7tf, 39%; 7xf, 32%) under otherwise
identical reaction conditions. The solid-state structure of 7uf
was also confirmed by single-crystal X-ray diffraction analysis,
from which we found that the acyl group appears to be trans to
the phenyl ring.11
To gain insight into the mechanism of this new cycloaddition
reaction, control experiments were conducted under the
standard reaction conditions. When the radical scavenger
TEMPO was introduced into the reaction system, no desired
product was obtained. Instead, the menaphthyl radical trapping
product 8 was observed in 32% isolated yield based on
TEMPO. These results support the idea that the menaphthyl
radical intermediate was most likely involved in the trans-
formation (see the SI). Moreover, kinetic isotope effect
experiments were conducted under the standard reaction
conditions (Scheme 3; see the SI). The competition reaction
of 2a and 2a-d3 revealed a significant isotope effect (kH/kD =
4.6), indicating that cleavage of the C(sp3)−H bond might be
involved in the rate-limiting step of this cycloaddition reaction.
On the other hand, the competition reaction of 2a and 2a-d7
showed a small isotope effect (kH/kD = 1.1), indicating that
cleavage of the C−H bond of the naphthalene is a fast process.
On the basis of the current results and computational
studies,9 a plausible reaction pathway for the formation of the
cycloadducts is depicted in Scheme 4. Initially, homolytic
fission of TBP by Cu(I) affords tert-butoxyl radical and Cu(II)
species with the assistance of the carboxylic acid.12 Hydrogen
abstraction from the methylnaphthalene by tert-butoxyl radical
Scheme 3. Intermediate Trapping and Kinetic Isotope Effect
Experiments
Scheme 4. Plausible Reaction Mechanism
generates t-BuOH and a menaphthyl radical, which then adds
to the alkene, giving radical intermediate A. The radical in A
site-selectively adds to the α-position of the naphthalene,
affording intermediate B.13 Finally, direct hydrogen-atom
transfer from B to tert-butoxyl radical forms the product, or
single-electron oxidation of B by Cu(II) generates a cation that
is then deprotonated by t-BuO− to deliver the desired product
3 and t-BuOH. Meanwhile, Cu(I) is regenerated to enter the
next catalytic cycle. Additionally, we assume that the
mechanism of the formal [3 + 2] cycloaddition is similar to
that of the formal [4 + 2] cycloaddition.
We then attempted to perform further derivatization of the
obtained products 3 to demonstrate their synthetic utility. In
the presence of Pd(OAc)2/PCy3/Cs2CO3, 3wa can be easily
converted to the polycyclic compound 9, a polycondensed odd-
alternant hydrocarbon,14 in 72% yield (Scheme 5). Interest-
Scheme 5. Synthetic Applications
ingly, the configuration of the acyl and phenyl groups is
changed from trans to cis in this transformation, most likely as a
result of keto−enol tautomerization initiated by Cs2CO3. The
solid-state structures of 3wa and 9 were unambiguously
determined by single-crystal X-ray diffraction analysis.11
In summary, we have identified that methylnapthenes not
only can be used as benzyl-type radical precursors for initiating
the radical addition reaction with electron-deficient alkenes but
also can function as radical acceptors to furnish a cycloaddition
reaction. This unique feature enables novel copper-catalyzed
highly diastereoselective and regioselective formal [4 + 2] and
C
DOI: 10.1021/acs.orglett.7b03194
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Experimental details and full spectroscopic data for all
new compounds (PDF)
Accession Codes
CCDC 1570579, 1570581, 1570583, 1570587, 1570588,
1570590, 1570596, and 1570597 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hanmin@ustc.edu.cn.
ORCID
Yong Wang: 0000-0002-7668-2234
Hanmin Huang: 0000-0002-0108-6542
Notes
(7) (a) Xie, P.; Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am.
Chem. Soc. 2012, 134, 9902. (b) Xie, P.; Xia, C.; Huang, H. Org. Lett.
2013, 15, 3370. (c) Qin, G.; Chen, X.; Yang, L.; Huang, H. ACS Catal.
2015, 5, 2882.
The authors declare no competing financial interest.
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1991, 56, 5328.
(9) Computational studies revealed that the energy of the
antibonding molecular orbital for the naphthalene is lower than that
of benzene by 21.9 kcal mol−1. See the Supporting Information for
details.
ACKNOWLEDGMENTS
■
This research was supported by the CAS Interdisciplinary
Innovation Team and the National Natural Science Foundation
of China (21672199).
́
(10) (a) Luis, J. G.; Echeverri, F.; Quinones, W.; Brito, I.; Lopez, M.;
̃
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